Glucocorticoid adjusts peripheral glucose metabolism and amino-acid metabolism. In human being, glucocorticoid is produced in adrenal glands, and in addition, it is metabolized in peripheral tissues such as adipose tissue or liver. Since 11βHSD1 is an enzyme which converts inactive cortisone into activated cortisol and is expressed mainly in adipose tissue or liver, 11βHSD1 is believed to have some relations to the activation of glucocorticoid in adipose tissue or liver. Since cortisol shows promoting activities for fat accumulation to adipocyte and for gluconeogenesis in liver, 11βHSD1 is believed to contribute to the maintenance of homeostasis in whole body by adjusting peripheral glucose and lipid metabolism. On the other hand, 11βHSD1 activity in adipose tissue significantly increases in insulin resistance patients in human being, and 11βHSD1 activity is remarkably higher in visceral fat than that in subcutaneous fat. Visceral fat accumulation and development of abnormal glucose and lipid metabolism are suppressed on high-fat diet feeding in 11βHSD1 gene defect mice, and adipose cell-specific 11βHSD1-overexpressed mice show remarkable visceral fat-type obesity or abnormal glucose and lipid metabolism. This indicates that overactivation of 11βHSD1 is intimately related to visceral fat accumulation and development of metabolic syndrome in human and mice (Nonpatent documents 1 and 2). In other words, suppression of gluconeogenesis in liver and fat accumulation in adipocyte, and improvement of glucose and lipid metabolism in whole body are expected by inhibiting this enzyme activity.
As far as the improvement of glucose metabolism, since it has been reported that 11βHSD1 activity in pancreatic β cells could contribute to the suppression of insulin secretion or 11βHSD1 activity in human muscle cells could have some relations to the suppression of glucose uptake of muscle cells, 11βHSD1 inhibitor has potential to remedy hyperglycemia directly.
11βHSD1 is also expressed in central nervous systems including hippocampus. It has been known that patients with Cushing's disease wherein glucocorticoid overexpresses and those whom a kind of synthetic glucocorticoids dexamethasone is administered show depression symptom. It has been also known that glucocorticoid receptor antagonist is effective for depression and manic depression, and it has been indicated that glucocorticoid in central nervous systems is intimately related to the expression of symptom of depression as well as manic depression (Nonpatent documents 3 and 4). Since 11βHSD1 plays a role in the production of active glucocorticoid in central nervous systems, it has been expected that 11βHSD1 inhibitor would show effectiveness in the treatment of depression and manic depression.
Furthermore, 11βHSD1 is indicated to have much relation to the adjustment of cognitive function, since depositions of amyloid β protein which is strongly indicated to relate to Alzheimer's dementia have been caused in mice to which glucocorticoid have been administered for a long term, and it is recognized that age-related cognitive function loss is inhibited and the increase of cognition maintenance is increased in 11βHSD1 gene defect mice (Nonpatent documents 5 to 7). The knowledge as shown above indicates that 11βHSD1 inhibitor is useful as a therapeutic agent of dementia including Alzheimer's dementia. Since it has been shown that 11βHSD1 functions in immunocytes, 11βHSD1 inhibitor is also expected to show therapeutic effectiveness in diseases caused by abnormal immune function.
Various 11βHSD1 inhibitors have been reported so far. For example, Patent document 1 discloses a compound of the following formula:
wherein R1 is hydrogen atom, etc., R2 is independently Ra, U is ═N—, etc., V is ═N—, etc., W is ═N—, etc., Y is ═N—, etc., Z is ═N—, etc., X is —N(H)—, —O—, —S—, —S(O)— or —S(O)2—, Ra is halogen, cyano, etc., p is 0, etc.
Patent document 2 discloses a compound of the following formula:
wherein R1 is hydrogen atom, etc., R2 is a group of the following formula:
etc., Q is —CH2OH, etc., R4 is hydrogen atom, etc., X1 is absent or —O—, —S—, —S(═O)—, —S(═O)2—, etc., X2 is absent or —O—, etc., X3 is absent or —O—, etc., R3 is substituted C1-6 alkyl, substituted C3-10 heterocyclyl, substituted aryl, substituted heteroaryl, —C(═O)R15, etc., R15 is hydrogen atom, halogen, C1-6 alkyl, C3-10 heterocyclyl, C3-10 cycloalkyl, aryl or heteroaryl, etc.
Compound groups disclosed in Patent documents 1 and 2 are compounds having adamantylaminocarbonyl skeletone with 11βHSD1 inhibitory activity. Nevertheless, compounds characterized by having a partial structure such as arylcarbonyl group or heteroarylcarbonyl group with the amide skeletone have never been specifically disclosed.    [Patent document 1] WO 2010/059618 pamphlet    [Patent document 2] WO 2008/101907 pamphlet    [Nonpatent document 1] Saishin Igaku, vol. 62, pp. 83-90, 2007    [Nonpatent document 2] Stimson et al., Minerva Endocrinology, 32, 141 (2007)    [Nonpatent document 3] Schatzberg et al., European Journal of Pharmacology, 583, 358 (2008)    [Nonpatent document 4] Herbert et al., Journal of Neuroendocrinology, 18, 393 (2006)    [Nonpatent document 5] Yau et al., Proceedings of the National Academy of Sciences, 98, 4716 (2001)    [Nonpatent document 6] Green et al., Journal of Neuroscience, 26(35), 9047 (2006)    [Nonpatent document 7] Yau et al., The Journal of Neuroscience, 27(39), 10487 (2007)